Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy Treatment & Management
- Author: Lawrence H Brent, MD; Chief Editor: Herbert S Diamond, MD more...
No definite disease-modifying treatment exists for individuals with ankylosing spondylitis (AS). Early diagnosis is important. As with any chronic disease, patient education is vital to familiarize the patient with the symptoms, course, and treatment of the disease. Treatment measures include pharmacologic, surgical, and physical therapy.
No drugs have been proved to modify the course of the disease, although tumor necrosis factor alpha (TNF-α) antagonists appear to have potential as disease-modifying agents. Symptoms are generally not affected by pregnancy or childbirth. Medical management of AS, including medications, must be adjusted during pregnancy in accordance with the specific pregnancy profiles of the medications.
Inpatient care is generally not necessary for patients with AS. The exceptions to this include patients with coexisting or extra-articular disease and those requiring surgery.
Patients with extra-articular manifestations must be treated properly or referred to an appropriate specialist. These extra-articular manifestations include acute anterior uveitis, aortitis, conduction defects, pulmonary fibrosis, amyloidosis, and neurologic deficits, including cauda equina. Disease progress and response to therapy can be monitored by following laboratory values, including the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level.
Surgical treatment is geared toward resolution of the complications related to AS; it is occasionally useful for correcting spinal deformities or repairing damaged peripheral joints. Patients with fusion of the spine secondary to AS who report a change in position of the spine should be cautiously treated and should be considered to have sustained a spinal fracture. Surgical intervention may be necessary to stabilize the fracture and prevent neurologic deficit.[92, 93]
Outpatient care should be aimed toward providing adequate pain control and maximizing motion and functional ability. Such care includes pain medication, exercise programs, recreational therapy, and vocational therapy. Regular exercise helps reduce the symptoms and may slow the progress of the disease. Generally, no dietary restrictions are implemented for patients with AS; however, patients with coexisting diseases, such as inflammatory bowel disease (IBD), have dietary restrictions.
Nonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) improve the symptoms of the disease by reducing pain and decreasing inflammation. Numerous choices are available, and they are separated into different families of agents. If one NSAID is ineffective, another from a different family can often provide relief.
Efficacy and adverse effect profiles differ among agents and families. Indomethacin may be more effective than other NSAIDs, although this potential advantage has not been proved. Salicylates seldom give adequate relief. Cyclooxygenase-2 (COX-2) inhibitors appear to be as effective as nonselective NSAIDs.
Sieper et al, in a randomized, double-blind, controlled study comparing two dosages of celecoxib (200 mg once daily and 200 mg twice daily) to diclofenac (75 mg twice daily), noted that both dosages of celecoxib were comparable to the diclofenac dosage with respect to global pain intensity. However, with respect to changes in disease activity, functional and mobility capacities, and adverse events, once-daily celecoxib was not as effective in reducing certain inflammation-associated parameters as twice-daily celecoxib and diclofenac were.
Give NSAIDs in full anti-inflammatory doses. Continuous treatment with NSAIDs appears to reduce radiographic progression in AS. Common toxicities involve the gastrointestinal (GI) tract (nausea, dyspepsia, ulceration, bleeding), the kidneys, and the central nervous system (CNS).
Sulfasalazine is useful in AS patients who do not respond to or who have contraindications to NSAIDs, as well as in those with coexisting IBD. In particular, it is often given to treat peripheral joint involvement, for which it has demonstrated efficacy. Sulfasalazine reduces spinal stiffness, peripheral arthritis, and the erythrocyte sedimentation rate (ESR), but there is no evidence that it improves spinal mobility, enthesitis, or physical function.[97, 98, 99] In a randomized, double-blind study, treatment with sulfasalazine resulted in significantly lesser improvement when compared to treatment with the TNF inhibitor etanercept. Sulfasalazine toxicities include rash, nausea, diarrhea, and agranulocytosis (rarely).
TNF is a cytokine with two identified forms, which have similar biologic properties. TNF-α (cachectin) is produced predominantly by macrophages, and TNF-β (lymphotoxin) is produced by lymphocytes. TNF is but one of many cytokines involved in the inflammatory cascade that may contribute to the symptoms of AS.[101, 94]
TNF-α antagonists have been shown to be beneficial in the treatment of AS. They are very effective, with a fairly rapid onset of action (2 weeks), and have been shown to reduce the inflammatory activity of spinal disease as assessed with magnetic resonance imaging (MRI).
The European League Against Rheumatism notes that extensive MRI inflammatory activity, particularly in the spine, might be used as a predictor of good clinical response to anti-TNF-alpha treatment in patients with AS. Thus, MRI might aid in the decision of initiating anti-TNF-alpha therapy, in addition to clinical examination and C-reactive protein (CRP) testing.
Etanercept,[104, 105] infliximab,[106, 107, 108] adalimumab, golimumab, and certolizumab pegol[111, 112] have all been approved by the US Food and Drug Administration (FDA) as therapies for AS and are indicated after NSAID therapy has failed. They are also approved for the treatment of rheumatoid arthritis and psoriatic arthritis (PsA). Some of them are approved for psoriasis (etanercept, infliximab, adalimumab, certolizumab pegol), juvenile idiopathic arthritis (etanercept, adalimumab), and Crohn disease (infliximab, adalimumab, certolizumab pegol).
Toxicities associated with TNF-α antagonists include injection-site and infusion reactions. Increased risks of bacterial infections, reactivation of latent tuberculosis, and certain fungal infections (eg, histoplasmosis, coccidioidomycosis) have been observed.
There is some concern regarding an increased risk of malignancy in patients receiving TNF-α antagonists. The most attention has been focused on lymphoma and nonmelanotic skin cancers in patients with rheumatoid arthritis, although this has been difficult to document in such patients and has not been described in patients with AS. In rare cases, cytopenias have been associated with TNF-α antagonists.
Patients with rheumatoid arthritis who have recently started TNF-α antagonists may be at increased risk for new-onset congestive heart failure even in the absence of any obvious risk factors for the disease. These agents should not be initiated in patients with uncompensated congestive heart failure.
Patients should be screened for latent tuberculosis, hepatitis B, and HIV infection before beginning TNF-α antagonist therapy. Although these agents should not be used in patients with active hepatitis B infection, they appear to be safe in patients with chronic hepatitis C infections. Rarely, autoimmune syndromes (eg, a lupuslike illness) have been noted in patients receiving TNF-α antagonists. More commonly, a positive antinuclear antibody (ANA) test result may occur during treatment without clinical disease.
Demyelinating syndromes have rarely been documented in patients receiving TNF-α antagonists, though no direct link has been proved. These agents should not be used in patients with multiple sclerosis or other demyelinating diseases. New-onset psoriatic skin lesions have been documented after initiation of TNF-α antagonists.
Results from a prospective study of 334 patients with AS indicated that treatment with tumor necrosis factor-α (TNF-α) inhibitors significantly reduced the risk of radiographic progression of AS. The investigators found that nearly 4 years of treatment were necessary for the benefit to become apparent and that starting TNF-inhibitor therapy late resulted in no benefit. The odds of progression were reduced by 50% in patients who responded to the TNF-inhibitor treatment. However, in patients who first began TNF-inhibitor treatment 10 or more years after disease onset, AS progression was twice as likely as it was in patients who started treatment earlier.[114, 115]
Secukinumab (Cosentyx) is a human IgG1 monoclonal antibody that selectively binds to and neutralizes the proinflammatory cytokine interleukin 17A (IL-17A). IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Secukinumab was approved by the FDA for adults with active ankylosing spondylitis in January 2016.
Approval of secukinumab for AS was based on 2 phase 3 trials (MEASURE 1 and 2). In MEASURE 1 (n=371), the Assessment of Spondyloarthritis International Society (ASAS20) response rates at week 16 were 61%, 60%, and 29% for SC secukinumab doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for both comparisons with placebo). In MEASURE 2 (n=219), the rates were 61%, 41%, and 28% for SC secukinumab doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for the 150-mg dose and P=0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks.
Oral corticosteroids are occasionally helpful in controlling AS symptoms. However they should be used only for short-term management; long-term management carries a high risk of adverse effects. No evidence has shown that corticosteroids alter the outcome of the disease, and these agents are known to increase the tendency toward spinal osteoporosis.
Local corticosteroid injections are useful for symptomatic sacroiliitis, peripheral enthesitis, and arthritis, although the response is not typically as rapid as in patients with rheumatoid arthritis.
Anecdotal reports suggest that other medications may be helpful in the treatment of AS, including methotrexate, azathioprine, cyclophosphamide, and cyclosporine. Methotrexate is of questionable benefit in AS; various studies have shown conflicting results. At present, it is reserved for patients with symptoms that are not adequately controlled with NSAIDs or sulfasalazine.
Leflunomide was evaluated in a randomized, double-blind, placebo-controlled study in active AS but was not found to be effective. Bisphosphonates may modestly affect clinical disease activity in AS. Anakinra, a recombinant human IL-1 receptor antagonist, may be effective in treatment-resistant AS.
Guidelines on treatment for ankylosing spondylitis and nonradiographic axial spondyloarthritis have been issued by the American College of Rheumatology.
In adults with active ankylosing spondylitis (AS):
Strongly recommend treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) over no treatment with NSAIDs.
Conditionally recommend continuous treatment with NSAIDs over on-demand treatment with NSAIDs.
No recommendation for any particular NSAID as the preferred choice.
Strongly recommend against treatment with systemic glucocorticoids.
In adults with active AS despite treatment with NSAIDs:
Conditionally recommend against treatment with slow-acting antirheumatic drugs (SAARDs).
Strongly recommend treatment with a tumor necrosis factor inhibitor (TNFi) over no treatment with TNFi.
No recommendation for any particular TNFi as the preferred choice.
In adults with active AS despite treatment with NSAIDs and who have contraindications to TNFi, conditionally recommend treatment with a SAARD over treatment with a non-TNFi biologic agent.
In adults with AS and inflammatory bowel disease:
No recommendation for any particular NSAID as the preferred choice to decrease the risk of worsening of inflammatory bowel disease symptoms.
Treatment with TNFi monoclonal antibodies strongly recommended over treatment with etanercept .
In adults with AS and isolated active sacroiliitis despite treatment with NSAIDs, conditionally recommend treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids.
In adults with AS with stable axial disease and active enthesitis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids. Peri-tendon injections of Achilles, patellar, and quadriceps tendons should be avoided.
In adults with AS with stable axial disease and active peripheral arthritis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids.
In adults with AS and advanced hip arthritis, strongly recommend treatment with total hip arthroplasty over no surgery.
In adults with AS and severe kyphosis, conditionally recommend against elective spinal osteotomy.
Treatment of Extra-articular Manifestations
Any extra-articular manifestations of AS are treated as dictated by the clinical setting.
Acute anterior uveitis presents as a painful red eye that is associated with photophobia and often recurs. Untreated uveitis may lead to vision loss. Evaluation and treatment of uveitis should be performed under the guidance of an ophthalmologist.
Generally, patients respond well to topical corticosteroids, mydriatics, and artificial tears, with resolution of the attack over 2-3 months. Treatment occasionally requires topical NSAIDs, retrobulbar corticosteroid injections, or immunosuppressive drugs. TNF-α antagonists may be helpful in selected cases. A study by van Denderen and colleagues reported a significant reduction in the recurrence rate of anterior uveitis in patients with AS who were treated with adalimumab.
Evaluation of Disease Activity and Treatment Response
Laboratory values, including the ESR and the C-reactive protein (CRP) level, are commonly employed to monitor the progression of the disease and the effectiveness of treatment. Guidelines from the European League Against Rheumatism (EULAR) recommend that conventional radiography of the sacroiliac (SI) joints, spine, or both may be used for long-term monitoring of structural damage, particularly new bone formation. If performed, it should not be repeated more frequently than every second year.
MRI may provide additional information. MRI of the SI joints and/or the spine may be used to assess and monitor disease activity in axial spondyloarthropathy. In general, short tau inversion recovery (STIR) sequences are sufficient to detect inflammation, and the use of contrast medium is not needed.
In addition, numerous tools have been developed to measure AS disease activity, especially in the setting of clinical trials.[119, 120, 121] These tools include the following:
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) - This is a questionnaire that assesses fatigue, pain (in the neck, back, and hip), peripheral joint pain and swelling, discomfort, and severity and duration of morning stiffness
Bath Ankylosing Spondylitis Functional Index (BASFI) - This is a questionnaire of physical function that evaluates dressing, bending, mobility, standing, stairs, and full-day activities
Bath Ankylosing Spondylitis Metrology Index (BASMI) - This is a physical evaluation of range of motion (ROM) of the cervical and lumbar spine
Assessment in Ankylosing Spondylitis (ASAS) - The ASAS core set of domains (parameters) measures disease activity and includes patient global assessment of disease activity, patient assessment of back pain, BASFI, morning stiffness, synovitis and enthesitis score, ESR, CRP level, and fatigue
The ASAS response criteria are used to assess improvement in AS in clinical trials. Each of four domains is scored by the patient on a visual analog scale ranging from 0 to 10. The four domains are as follows:
Patient global assessment of disease activity for the past week
Patient assessment of back over the past week
Inflammation (severity and duration of morning stiffness)
An ASAS20 response is defined as an improvement of at least 20% and an absolute improvement of at least 1 unit (on a 0-10 scale) in at least three of four domains, with no worsening of the remaining domain. An ASAS40 response is similar but requires a 40% improvement. An ASAS partial remission is defined as values of less than 2 for all four ASAS20 domains.
ASAS5/6 includes the four domains included in the ASAS20 plus spinal mobility (BASMI) and acute-phase reactants (CRP). An ASAS5/6 response is defined as improvement of at least 20% and an improvement of at least 1 unit in at least five of six domains, with no worsening of the remaining domain.
Surgical Correction and Stabilization
Patients with fusion of the cervical or upper thoracic spine may have significant impairment in line of sight, eating, and psychosocial well-being. These patients may benefit from extension osteotomy of the cervical spine. This procedure is difficult and hazardous and should be performed only by surgeons specializing in spine surgery who have experience with the operation. The risk of major neurologic morbidity is significant; however, if the procedure is successful, it allows the patient to return to a more functional life.
Many patients with advanced disease have fusion of the spine. If these patients report any change in position or movement of the spine, they should be assumed to have a spinal fracture because such an injury is the only way for a fused spine to move. Patients should be treated cautiously until fracture has been ruled out. If spinal fracture is present, surgical stabilization may be necessary.
Patients with significant involvement of the hips may benefit from total hip arthroplasty ; occasionally, total shoulder replacement may be indicated. These procedures may be very useful for reducing pain and improving function when the hip and shoulder joints become severely damaged.
Heterotopic bone formation may occur after total joint replacement, especially around the hip. Heterotopic bone formation can be reduced by giving NSAIDs (eg, indomethacin) or employing radiation therapy postoperatively. In general, outcomes of total joint replacement in patients have been satisfactory.
Physical Therapy and Exercise
Physical therapy is important for maintaining function.[122, 123] A proper exercise program is a crucial component of such therapy. Patients obtain a significant reduction in symptoms after exercising. Referral to physical therapy or to a rehabilitation specialist is useful in assisting patients to develop an appropriate exercise program. Water therapy and swimming are excellent activities for maintaining mobility and fitness.
Postural training is also useful. Spinal extension and deep-breathing exercises help maintain spinal mobility, encourage erect posture, and promote chest expansion. Maintaining an erect posture during daily activities and sleeping on a firm mattress with a thin pillow also tend to reduce the tendency toward thoracic kyphosis.
Consultations with the following specialists may be appropriate:
Rheumatologist - This consultation is indicated for evaluation and management of ongoing medical treatment of patients with AS; additional coexisting spondyloarthropathies can be assessed
Ophthalmologist - This consultation is indicated for patients with symptoms of acute anterior uveitis
Gastroenterologist - This consultation is indicated for patients with symptoms suggesting coexisting IBD
Cardiologist - This consultation is indicated for patients with cardiac involvement, including aortitis or heart block
Physical therapist or physical medicine and rehabilitation specialist - This consultation is indicated for all patients
Surgeon (orthopedic, neurologic, or both)
Geneticist - Patients may be referred for genetic counseling to assess questions regarding the probabilities of relatives developing the disease
Support groups - Many patients benefit from various support groups, which can provide further education on the disease process and available treatment options
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- Table 1. Association of Spondyloarthropathies With HLA-B27
- Table 2. Genetics of Ankylosing Spondylitis
- Table 3. Diagnostic Criteria for Undifferentiated Spondyloarthropathy Using Modified Amor Criteria
- Table 4. Clinical and Laboratory Features of Undifferentiated Spondyloarthropathy
- Table 5. ESSG and Amor Criteria for Diagnosis of Spondyloarthropathy
- Table 6. New York and Rome Criteria for Diagnosis of Ankylosing Spondylitis
|Population or Disease Entity||HLA-B27 –Positive|
|Healthy African Americans||4%|
|Ankylosing spondylitis (whites)||92%|
|Ankylosing spondylitis (African Americans)||50%|
|Psoriasis associated with spondylitis||60%|
|IBD associated with spondylitis||60%|
|Isolated acute anterior uveitis||50%|
|Genes||Chromosome Location||Gene Product/Function|
IL-1 gene cluster
Modulator of inflammation
Metabolism of xenobiotics
ER aminopeptidase 1
TGF-ß, MMP3, IL-10, IL-6, Ig allotypes, TCR, TLR4, NOD2/CARD15, CD14, NFßBIL1, PTPN22, etc
|Inclusion Criteria||Exclusion Criteria|
|Inflammatory back pain||1 point||Diagnosis of specific spondyloarthropathy|
|Unilateral buttock pain||1 point||Sacroiliitis on radiograph = grade 2|
|Alternating buttock pain||2 points||Precipitating genitourinary/gastrointestinal infection|
|Peripheral arthritis||2 points||Keratoderma blennorrhagicum|
|Dactylitis (sausage digit)||2 points||Inflammatory bowel disease (Crohn disease or ulcerative colitis)|
|Acute anterior uveitis||2 points||Positive rheumatoid factor|
|HLA-B27 –positive or family history of spondyloarthropathy||2 points||Positive antinuclear antibody, titer > 1:80|
|Good response to nonsteroidal anti-inflammatory drugs||2 points|
|Diagnosis of spondyloarthropathy with 6 or more points|
|Clinical or Laboratory Feature||Frequency|
|Inflammatory back pain||90%|
|Dactylitis (sausage digits)||20%|
|Acute anterior uveitis||1-2%|
|ESR = erythrocyte sedimentation rate.|
|ESSG Criteria||Amor Criteria*|
|Inflammatory spinal pain or synovitis and one of the following:||Inflammatory back pain||1 point|
|Alternating buttock pain||Unilateral buttock pain||1 point|
|Enthesitis||Alternating buttock pain||2 points|
|IBD||Peripheral arthritis||2 points|
|Positive family history of spondyloarthropathy||Dactylitis (sausage digit)||2 points|
|Acute anterior uveitis||2 points|
|HLA-B27 –positive or family history of spondyloarthropathy||2 points|
|Good response to NSAIDs||2 points|
|*Diagnosis of spondyloarthropathy with 6 or more points.
European Spondyloarthropathy Study Group (ESSG); IBD = inflammatory bowel disease; NSAID = nonsteroidal anti-inflammatory drug.
|New York Criteria||Rome Criteria|
|Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria||Diagnosis of ankylosing spondylitis when any clinical criteria present with bilateral sacroiliitis grade 2 or higher|